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With the in-depth knowledge of the pathological and physiological characteristics of the intestinal barrier-portal vein/intestinal lymphatic vessels-systemic circulation axis, oral targeted drug delivery is frequently being renewed. With many advantages, such as high safety, convenient administration, and good patient compliance, many researchers have begun to explore targeted drug delivery from intravenous injections to oral administration. Over the past few decades, the fields of materials science and nanomedicine have produced various drug delivery platforms that hold great potential in overcoming the multiple barriers associated with oral drug delivery. However, the oral transport of particles into the systemic circulation is extremely difficult due to immune rejection and biochemical invasion in the intestine, which limits absorption and entry into the bloodstream. The feasibility of the oral delivery of targeted drugs to sites outside the gastrointestinal tract (GIT) is unknown. This article reviews the biological barriers to drug absorption, the in vivo fate and transport mechanisms of drug carriers, the theoretical basis for oral administration, and the impact of carrier structural evolution on oral administration to achieve this goal. Finally, this article reviews the characteristics of different nano-delivery systems that can enhance the bioavailability of oral therapeutics and highlights their applications in the efficient creation of oral anticancer nanomedicines., Competing Interests: The authors declare no conflicts of interest in this work., (© 2024 Zhang et al.)

Purpose: The clinical application of immune checkpoint inhibitors (ICIs) has significantly improved the prognosis of liver cancer patients. However, drug eruption associated with ICI monotherapy or combination therapy not only impacts the quality of life and treatment progress of liver cancer patients but also poses a potential threat to their lives. The study aims to investigate the risk factors of drug eruption in liver cancer patients undergoing ICIs in real-world settings., Methods: We retrospectively collected data from liver cancer patients who underwent ICI therapies at the Third Affiliated Hospital of Sun Yat-sen University between 2021 and 2022. A propensity score matching (PSM) method was employed to match 31 liver cancer patients with ICI-related drug eruption (drug eruption group) to 228 liver cancer patients without immune-related adverse reactions (control group) in a 1:2 ratio, creating two groups of patients with comparable baseline characteristics. Subsequently, logistic regression analysis was then conducted to analyze the clinical risk factors associated with drug eruption caused by ICIs., Results: Before PSM, there were statistically significant differences between the drug eruption group (31 cases) and the control group (228 cases) in two variables: Child-Pugh liver function classification and presence of vascular invasion (both p  < 0.05). However, after PSM, no statistically significant differences were found in the clinical variables between the drug eruption group (28 cases) and the control group (52 cases). Univariate analysis revealed significantly higher levels of aspartate amino-transferase, alanine aminotransferase, glutamyl transpeptidase, and systemic immune-inflammation index (SII) and a significantly lower rate of liver cancer resection surgery before immunotherapy in liver cancer patients with drug eruption compared to the control group ( p  < 0.05). Multivariate analysis indicated that an elevated SII level before immunotherapy was significantly associated with the occurrence of drug eruption in liver cancer patients treated with ICIs ( p  < 0.05). The predictive performance of SII before immunotherapy in liver cancer patients for ICI-related drug eruption yielded an area under the receiver operator characteristic curve of 0.852, with a critical value of 749.189. Sensitivity and specificity were determined as 85.7% and 75%, respectively ( p  < 0.05)., Conclusions: Elevated systemic immune-inflammation index is identified as a risk factor for drug eruption occurrence in liver cancer patients treated with ICI therapies.

Background: Calculus bovis (CB), used in traditional Chinese medicine, exhibits anti-tumor effects in various cancer models. It also constitutes an integral component of a compound formulation known as Pien Tze Huang, which is indicated for the treatment of liver cancer. However, its impact on the liver cancer tumor microenvironment, particularly on tumor-associated macrophages (TAMs), is not well understood., Aim: To elucidate the anti-liver cancer effect of CB by inhibiting M2-TAM polarization via Wnt/β-catenin pathway modulation., Methods: This study identified the active components of CB using UPLC-Q-TOF-MS, evaluated its anti-neoplastic effects in a nude mouse model, and elucidated the underlying mechanisms via network pharmacology, transcriptomics, and molecular docking. In vitro assays were used to investigate the effects of CB-containing serum on HepG2 cells and M2-TAMs, and Wnt pathway modulation was validated by real-time reverse transcriptase-polymerase chain reaction and Western blot analysis., Results: This study identified 22 active components in CB, 11 of which were detected in the bloodstream. Preclinical investigations have demonstrated the ability of CB to effectively inhibit liver tumor growth. An integrated approach employing network pharmacology, transcriptomics, and molecular docking implicated the Wnt signaling pathway as a target of the antineoplastic activity of CB by suppressing M2-TAM polarization. In vitro and in vivo experiments further confirmed that CB significantly hinders M2-TAM polarization and suppresses Wnt/β-catenin pathway activation. The inhibitory effect of CB on M2-TAMs was reversed when treated with the Wnt agonist SKL2001, confirming its pathway specificity., Conclusion: This study demonstrated that CB mediates inhibition of M2-TAM polarization through the Wnt/β-catenin pathway, contributing to the suppression of liver cancer growth., Competing Interests: Conflict-of-interest statement: The authors declare that they have no competing interests to disclose., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: The escalating prevalence of metabolic diseases has led to a rapid increase in non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (NASH-HCC). While oxaliplatin (OXA)-based hepatic arterial infusion chemotherapy (HAIC) has shown promise in advanced-stage HCC patients, its efficacy in NASH-HCC remains uncertain. This study aims to assess the effectiveness of OXA-based HAIC and elucidate the mechanisms underlying OXA resistance in NASH-HCC., Methods: The key lncRNAs were screened through RNA-seq analysis of NASH/non-NASH and OXA-sensitive/OXA-resistant (OXA-S/R) HCC tissues. The biological functions of the lnc-OXAR (OXA resistance-related lncRNA in NASH-HCC) in NASH-HCC were verified through a series of in vitro and in vivo experiments. The molecular mechanism of lnc-OXAR was elucidated by fluorescence in situ hybridization, immunoprecipitation-mass spectrometry (FISH), Immunoprecipitation-Mass Spectrometry (IP-MS), RNA pulldown, RNA immunoprecipitation (RIP), methylated RNA immunoprecipitation sequencing (MeRIP-Seq) and a dual-luciferase reporter assay., Results: NASH-HCC exhibited reduced responsiveness to OXA-based HAIC compared to non-NASH HCC. We identified and validated a novel transcript namedlnc-OXAR, which played a crucial role in conferring OXA resistance to NASH-HCC. Inhibition of lnc-OXAR suppressed HCC cell growth and restored OXA sensitivity both in NASH-HCC mouse models and in vitro. Mechanistically, lnc-OXAR recruited Ku70 and cystatin A (CSTA), preventing Ku70 degradation and facilitating DNA double-strand break (DSB) repair, thereby promoting OXA resistance in NASH-HCC. Additionally, WTAP-mediated m 6 A modification enhanced the stability of lnc-OXAR in an IGF2BP2-dependent manner. Notably, silencing lnc-OXAR significantly enhanced the response to OXA in patient-derived xenograft (PDX) models derived from NASH-HCC., Conclusions: The reduced responsiveness of NASH-HCC to OXA treatment can be attributed to the upregulation of lnc-OXAR. Our findings provide a rationale for stratifying HCC patients undergoing OXA-based HAIC based on etiology. Lnc-OXAR holds promise as a novel target for overcoming OXA resistance in NASH-HCC and improving prognosis., (© 2024. The Author(s).)

Background: Mirror syndrome is a rare disease characterized by "triple edema", while Hemolytic Uremic Syndrome (PHUS) is a serious disease that occurs within a short period of time after the end of pregnancy, with a low prevalence and poor prognosis, and it is even rarer for both to occur in the same patient., Methods: We report a case of mirror syndrome combined with PHUS and analyze the clinical data to improve the understanding of the disease., Results: The patient presented clinically with "triple edema" and was diagnosed with mirror image syndrome. After cesarean section, the patient developed cardiac insufficiency, renal insufficiency, hemolysis, and other symptoms and was diagnosed as PHUS. After active treatment, the maternal prognosis was good., Conclusions: Mirror syndrome and PHUS are both clinically rare diseases with poor long-term prognosis if not diagnosed and treated in a timely manner; therefore, awareness of the diseases, early and accurate diagnosis and timely and correct treatment should be improved.

In a recent Nature elegant study, Wang et al. identified CD300ld, a novel functionally highly conserved tumor immunosuppressive receptor, highly expressed specifically on polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), as well as a key receptor in the regulation of recruitment and immunosuppressive function of PMN-MDSCs. Targeting CD300ld could remodel the tumor immune microenvironment, resulting in a broad-spectrum anti-tumor effect., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.)

Purpose: To characterize the phenotype and genotype of a Chinese family with autosomal-dominant retinitis pigmentosa (RP) accompanied by iris coloboma., Methods: The proband, a 34-year-old male, was examined with his family by using fundus photography, optical coherence tomography (OCT), autofluorescence, and full-field electroretinography (ffERG). Genetic analyses were conducted through whole-exome sequencing (WES) to screen for variations., Results: Three members of this Chinese family were shown to be bilateral iris coloboma. The male proband and his mother exhibited typical RP feature. The proband's late grandfather had been documented manifestation of iris coloboma. The mode of inheritance was confirmed to be autosomal dominance. Through linkage analysis and WES, a heterozygous variation in the miR-204 gene (n.37C>T), a noncoding RNA gene, was identified in these three members., Conclusions: In this third independent and the first Asian family, the existence of a miR-204 variant associated with RP accompanied by iris coloboma was confirmed. Our findings reinforce the significance of miR-204 as an important factor influencing visual function in the retina. When phenotypes like RP accompanied by iris coloboma in an autosomal-dominant pattern, including in Chinese patients, miR-204 aberrations should be considered., (© 2024 The Author(s). Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Background: The optimal subsequent management for patients with initially unresectable hepatocellular carcinoma (uHCC) who have achieved complete response (CR) following conversion therapy remains unclear. This study aims to evaluate the feasibility and outcomes of the watch-and-wait (W-W) strategy versus surgical resection (SR) for these patients., Materials and Methods: This retrospective study reviewed patients with initially uHCC who underwent conversion therapy employing transarterial therapies combined with or without systemic therapies. Radiologic CR (rCR), clinical CR (cCR), and pathologic CR (pCR) were evaluated. Overall survival (OS) and progression-free survival (PFS) were compared between the W-W and SR groups., Results: Among 1880 patients with uHCC who underwent conversion therapy, 207 (11.0%) achieved rCR. Finally, we enrolled 149 patients meeting the inclusion criteria, including 74 receiving W-W strategy and 75 undergoing SR. Among the 149 patients with rCR, the W-W group demonstrated comparable 3-year OS rates to the SR group (80.9 vs 83.1%, P =0.77), but demonstrated inferior PFS rates (14.4 vs 46.5%, P =0.002). These results remained consistent after propensity score matching. For the 57 patients who achieved cCR, the W-W group exhibited comparable 3-year OS (88.1 vs 87.9%, P =0.89) and PFS rates (27.8 vs 40.8%, P =0.34) compared to SR group. Among the 75 patients in the SR group, 31 (41.3%) achieved pCR and 44 (58.7%) reached non-pCR. When compared with patients with pCR, those who achieved rCR in the W-W group showed comparable OS but inferior PFS rates. Moreover, patients who achieved rCR in the W-W group displayed both comparable OS and PFS rates to those with non-pCR., Conclusion: The W-W strategy offered comparable survival outcomes to SR in patients with initially uHCC who achieved rCR or cCR after conversion therapy. For these patients, the W-W strategy could be offered as an alternative treatment option., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Abstract: The comprehensive management of a patient with chronic graft-versus-host disease skin ulcers after hematopoietic stem cell transplantation is challenging. This report describes the case of a 53-year-old woman who presented with ulcers on her right leg 140 weeks after a bone marrow transplant. The patient received wound assessment and management based on the Triangle of Wound Assessment and Wound Bed Preparation 2021, respectively. Hydrogel and antibacterial protease dressings were applied along with systemic oral administration of moxifloxacin hydrochloride (two capsules, two times daily) and JiXueGanPian tablets (classic Chinese herbal formula; two capsules, two times daily), hospital-community-home continuous care, and patient-centered education. Finally, after 133 days of nursing, the patient's wound was completely healed without complications or other skin issues. The use of hydrogel combined with the antibacterial protease dressing was a promising technique for handling this type of wound, enhanced by multidisciplinary collaboration. Of course, providing patients with education that focuses on prevention is necessary., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Minimally invasive pancreatic resections are gaining popularity despite being technically demanding. However, in contrast to laparoscopic pancreatoduodenectomy (LPD), laparoscopic duodenum-preserving pancreatic head resection (LDPPHR) has not yet obtained wide acceptance. This could be attributed to the technical challenges involved in preserving the blood supply of the duodenum and bile duct. This study describes and demonstrates all the steps of LDPPHR. A 48-year-old woman was diagnosed with a 3.0 cm x 2.5 cm pancreatic head cystic mass, which was detected unexpectedly. The surgery was performed using the 3D laparoscopy via an inferior infracolic approach. The operation lasted approximately 310 min with 100 mL of blood loss. Postoperatively, the patient experienced no complications and was discharged 5 days later. Pathology revealed intraductal papillary mucinous neoplasms. LDPPHR via an inferior infracolic approach is feasible and safe when performed by experienced surgeons in selected patients with thin mesenteric fat layers. The described technique for LDPPHR via inferior infracolic approach should be well standardized and performed at high-volume centers with experienced surgeons in both open and laparoscopic pancreatology.

Background: Hepatocellular carcinoma (HCC) cells undergo reprogramming of glucose metabolism to support uncontrolled proliferation, of which the intrinsic mechanism still merits further investigation. Although regulatory factor X6 (RFX6) is aberrantly expressed in different cancers, its precise role in cancer development remains ambiguous., Methods: Microarrays of HCC tissues were employed to investigate the expression of RFX6 in tumour and adjacent non-neoplastic tissues. Functional assays were employed to explore the role of RFX6 in HCC development. Chromatin immunoprecipitation, untargeted metabolome profiling and sequencing were performed to identify potential downstream genes and pathways regulated by RFX6. Metabolic assays were employed to investigate the effect of RFX6 on glycolysis in HCC cells. Bioinformatics databases were used to validate the above findings., Results: HCC tissues exhibited elevated expression of RFX6. High RFX6 expression represented as an independent hazard factor correlated to poor prognosis in patients with HCC. RFX6 deficiency inhibited HCC development in vitro and in vivo, while its overexpression exerted opposite functions. Mechanistically, RFX6 bound to the promoter area of phosphoglycerate mutase 1 (PGAM1) and upregulated its expression. The increased PGAM1 protein levels enhanced glycolysis and further promoted the development of HCC., Conclusions: RFX6 acted as a novel driver for HCC development by promoting aerobic glycolysis, disclosing the potential of the RFX6-PGAM1 axis for therapeutic targeting., (© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Background and Aims: Metastasis is a major factor associated with high recurrence and mortality in hepatocellular carcinoma (HCC) patients while the underlying mechanism of metastasis remains elusive. In our study, procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) was shown to be involved in the process of metastasis in HCC., Methods: The Cancer Genome Atlas (TCGA) database and HCC tissue microarrays were used to evaluate the expression of genes. In vitro migration, invasion, in vivo subcutaneous tumor model and in vivo lung metastasis assays were used to determine the role of PLOD2 in tumor growth and metastasis in HCC. RNA sequencing and gene set enrichment analysis were performed to uncover the downstream factor of PLOD2 in HCC cells. A luciferase reporter assay was performed to evaluate the interaction between PLOD2 and interferon regulatory factor 5 (IRF5)., Results: The expression of PLOD2 in HCC tissues was higher than that in adjacent tissues, and increased PLOD2 expression was often found in advanced tumors and was correlated with poor prognosis in HCC patients. In vitro experiments, knockdown of PLOD2 reduced the migration and invasion of human HCC cells. Loss of PLOD2 suppressed human HCC growth and metastasis in a subcutaneous tumor model and a lung metastasis model. Baculoviral IAP repeat containing 3 (BIRC3) was proven to be the downstream factor of PLOD2 in human HCC cells. In addition, PLOD2 was transcriptionally regulated by IRF5 in HCC cells., Conclusions: High expression of PLOD2 was regulated by IRF5, which was correlated with the poor survival of HCC patients. PLOD2 enhanced HCC metastasis via BIRC3, suggesting that PLOD2 might be a valuable prognostic biomarker for HCC treatment., Competing Interests: The authors have no conflict of interests related to this publication., (© 2023 Authors.)

Lead halide perovskites have made remarkable progress in the field of radiation detection owing to the excellent and unique optoelectronic properties. However, the instability and the toxicity of lead-based perovskites have greatly hindered its practical applications. Alternatively, lead-free perovskites with high stability and environmental friendliness thus have fascinated significant research attention for direct X-ray detection. In this review, the current research progress of X-ray detectors based on lead-free halide perovskites is focused. First, the synthesis methods of lead-free perovskites including single crystals and films are discussed. In addition, the properties of these materials and the detectors, which can provide a better understanding and designing satisfactory devices are also presented. Finally, the challenge and outlook for developing high-performance lead-free perovskite X-ray detectors are also provided., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

In today's information age, high performance nonvolatile memory devices have become extremely important. Despite their potential, existing devices suffer from limitations, such as low operation speed, low memory capacity, short retention time, and a complex preparation process. To overcome these limitations, advanced memory designs are required to improve speed, memory capacity, and retention time and reduce the number of preparation steps. Here, we present a nonvolatile floating-gate-like memory device based on a transistor that uses the polarization effect of ferroelectric material PZT (Pb[Zr 0.2 Ti 0.8 ]O 3 ) for regulating tunneling electrons for charging and discharging the MoS 2 channel layer. The transistor is defined as a polarized tunneling transistor (PTT) and does not require a tunnel layer or a floating-gate layer. The PTT demonstrates an ultrafast programming/erasing speed of 25/20 ns and a response time of 120/105 ns, which is comparable to the ultrafast flash memories based on van der Waals heterostructures. Additionally, the PTT has a high extinction ratio of 10 4 , a long retention time of 10 years, and a simple fabrication process. Our research provides future guidelines for the development of the next generation of ultrafast nonvolatile memory devices.

Carbon anions formed via the addition of Grignard reagents to S P -vinyl phosphinates were modified with electrophilic reagents to afford organophosphorus compounds with diverse carbon skeletons. The electrophiles included acids, aldehydes, epoxy groups, chalcogens and alkyl halides. When alkyl halides were used, bis-alkylated products were afforded. Substitution reactions or polymerization occurred when the reaction was applied to vinyl phosphine oxides., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Based on metabolomics, to study the mechanism of Radix Wikstroemia indica (RWI) "Sweat soaking method" processing detoxification. The raw drug group and processed products was given raw RWI and processed RWI respectively by gavage. The control group was given the same amount of 1% sodium carboxy methyl cellulose distilled water by gavage. After 7 days of continuous gavage, blood samples were collected. The blood samples of rats in each group were analyzed by 1 H-NMR technology to explore the changes of endogenous metabolism and the possible metabolic pathways to rats before and after processing. Compared with the control group, the raw RWI could significantly reduce 16 metabolites and increase 10 metabolites. The processed RWI can increase the levels of most metabolites that decrease to the raw RWI, such as 13 metabolites such as alanine, L-glutamine, L-valine, L-serine, betaine and glutamic acid; At the same time, the metabolites that increased in the level of crude products were down-regulated, such as asparagine, lactic acid, 2-hydroxyisobutyric acid, sucrose, glucose and D-glucose. Compared with raw products, RWI treated with "Sweat soaking method" can reversely regulate or reduce amino acid, choline metabolism, energy and carbohydrate metabolism, thereby reducing hepatotoxicity and nephrotoxicity.

Background: The long-term survival of patients with hepatocellular carcinoma (HCC) with portal vein tumour thrombus (PVTT) is poor. Systemic therapy, transcatheter arterial chemoembolization (TACE), and hepatic artery infusion chemotherapy are widely used in HCC patients with PVTT. This study aims to explore the efficacy of combining systemic therapy with transarterial-based therapy in HCC patients with PVTT., Materials and Methods: The authors retrospectively reviewed data of HCC patients with PVTT treated with combination therapy (TACE-hepatic artery infusion chemotherapy with tyrosine kinase inhibitors and PD-1 inhibitors) or TACE alone in SYSUCC from 2011 to 2020. The overall survival (OS), progression-free survival, and overall response rate were compared. Propensity score matching was used to minimize confounding bias., Results: A total of 743 HCC patients with PVTT received combination therapy ( n =139) or TACE alone ( n =604). After propensity score matching, the overall response rate was significantly higher in the combination group than in the TACE group [42.1% vs. 5.0%, P < 0.001 (response evaluation criteria in solid tumours); 53.7% vs. 7.8%, P < 0.001 (modified response evaluation criteria in solid tumours)]. The combination group showed significantly better OS than the TACE group (median OS not reached vs. 10.4 months, P < 0.001). The median progression-free survival of the combination and TACE groups was 14.8 and 2.3 months ( P < 0.001), respectively. Tumour downstaging followed by salvage liver resection was significantly more common for the combination therapy group than for TACE group (46.3% vs. 4.5%, P < 0.001). After salvage liver resection, 31.6% (30/95) and 1.7% (3/179) of the patients achieved a pathological complete response in the combination and TACE groups, respectively ( P < 0.001). The grade 3/4 adverse events rates were similar between the two groups (28.1% vs. 35.9%, P =0.092)., Conclusion: Compared with TACE alone, combination therapy was safe enough and resulted in survival benefits. This is a promising treatment option for HCC patients with PVTT., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Although oxaliplatin-based chemotherapy has been effective in the treatment of hepatocellular carcinoma (HCC), primary or acquired resistance to oxaliplatin remains a major challenge in the clinic. Through functional screening using CRISPR/Cas9 activation library, transcriptomic profiling of clinical samples, and functional validation in vitro and in vivo, we identify PRMT3 as a key driver of oxaliplatin resistance. Mechanistically, PRMT3-mediated oxaliplatin-resistance is in part dependent on the methylation of IGF2BP1 at R452, which is critical for the function of IGF2BP1 in stabilizing the mRNA of HEG1, an effector of PRMT3-IGF2BP1 axis. Also, PRMT3 overexpression may serve as a biomarker for oxaliplatin resistance in HCC patients. Collectively, our study defines the PRTM3-IGF2BP1-HEG1 axis as important regulators and therapeutic targets in oxaliplatin-resistance and suggests the potential to use PRMT3 expression level in pretreatment biopsy as a biomarker for oxaliplatin-resistance in HCC patients., (© 2023. The Author(s).)

Background: Non-homologous DNA end joining (NHEJ) is the predominant DNA double-strand break (DSB) repair pathway in human. However, the relationship between NHEJ pathway and hepatocellular carcinoma (HCC) is unclear. We aimed to explore the potential prognostic role of NHEJ genes and to develop an NHEJ-based prognosis signature for HCC., Methods: Two cohorts from public database were incorporated into this study. The Kaplan-Meier curve, the Least absolute shrinkage and selection operator (LASSO) regression analysis, and Cox analyses were implemented to determine the prognostic genes. A NHEJ-related risk model was created and verified by independent cohorts. We derived enriched pathways between the high- and low-risk groups using Gene Set Enrichment Analysis (GSEA). CIBERSORT and microenvironment cell populations-counter algorithm were used to perform immune infiltration analysis. XRCC6 is a core NHEJ gene and immunohistochemistry (IHC) was further performed to elucidate the prognostic impact. In vitro proliferation assays were conducted to investigate the specific effect of XRCC6., Results: A novel NHEJ-related risk model was developed based on 6 NHEJ genes and patients were divided into distinct risk groups according to the risk score. The high-risk group had a poorer survival than those in the low-risk group (P < 0.001). Meanwhile, an obvious discrepancy in the landscape of the immune microenvironment also indicated that distinct immune status might be a potential determinant affecting prognosis as well as immunotherapy reactiveness. High XRCC6 expression level associates with poor outcome in HCC. Moreover, XRCC6 could promote HCC cell proliferation in vitro., Conclusions: In brief, this work reveals a novel NHEJ-related risk signature for prognostic evaluation of HCC patients, which may be a potential biomarker of HCC immunotherapy., (© 2023. The Author(s).)

Background: Metformin, a first-line oral anti-diabetic drug, has recently been reported to exert protective effect on various cardiovascular diseases. However, the potential role of metformin in ethanol-induced cardiomyocyte injury is still unknown. Therefore, this study was aimed to investigate the effect of metformin on ethanol-induced cardiomyocyte injury and its underlying mechanism., Methods and Results: H9c2 cardiomyocytes were exposed to ethanol for 24 h to establish an ethanol-induced cardiomyocyte injury model, and followed by treatment with metformin in the presence or absence of Lapatinib (an ErbB2 inhibition). CCK8 and LDH assays demonstrated that metformin improved cell viability in cardiomyocytes exposed to ethanol. Furthermore, metformin suppressed cardiomyocyte apoptosis and reduced the expressions of apoptosis-related proteins (Bax and C-CAS-3). In addition, our results showed that metformin activated the AKT/Nrf2 pathway, and then promoted Nrf2 nuclear translocation and the transcription of its downstream antioxidant genes (HO-1, CAT and SOD2), thereby inhibiting oxidative stress. Interestingly, we found that ErbB2 protein expression was significantly inhibited in ethanol-treated cardiomyocytes, which was markedly reversed by metformin. In contrast, Lapatinib largely abrogated the activation of AKT/Nrf2 signaling by metformin, accompanied by the increases in oxidative stress and cardiomyocyte apoptosis, indicating that metformin prevented ethanol-induced cardiomyocyte injury in an ErbB2-dependent manner., Conclusion: In summary, our study provides the first evidence that metformin protects cardiomyocyte against ethanol-induced oxidative stress and apoptosis by activating ErbB2-mediated AKT/Nrf2 signaling. Thus, metformin may be a potential novel treatment approach for alcoholic cardiomyopathy., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

An efficient triflic anhydride promoted phosphorylation of ketone was disclosed, and vinylphosphorus compounds were prepared under solvent- and metal-free conditions. Both aryl and alkyl ketones could perform smoothly to give vinyl phosphonates in high to excellent yields. In addition, the reaction was easy to carry out and easy to scale up. Mechanistic studies suggested that this transformation might involve nucleophilic vinylic substitution or a nucleophilic addition-elimination mechanism.

Objective: This study aims to screen for measures and lipid-derived indicators associated with insulin resistance (IR) in obese children and adolescents and develop a nomogram model for predicting the risk of insulin resistance., Methods: A total of 404 eligible obese children and adolescents aged 10-17 years were recruited for this study from a summer camp between 2019 and 2021. The risk factors were screened using the least absolute shrinkage and selection operator (LASSO)-logistic regression model, and a nomogram model was developed. The diagnostic value of the model was evaluated by plotting the receiver operator characteristic curve and calculating the area under the curve. Internal validation was performed using the Bootstrap method, with 1000 self-samples to evaluate the model stability. The clinical applicability of the model was assessed by plotting the clinical decision curve., Results: On the basis of the LASSO regression analysis results, three lipid-related derivatives, TG/HDL-c, TC/HDL-c, and LDL-c/HDL-c, were finally included in the IR risk prediction model. The nomogram model AUC was 0.804 (95% CI: 0.760 to 0.849). Internal validation results show a C-Index of 0.799, and the mean absolute error between the predicted and actual risks of IR was 0.015. The results of the Hosmer-Lemeshow goodness-of-fit test show a good model prediction (χ 2  = 9.523, P = 0.300)., Conclusion: Three early warning factors, TG/HDL-c, TC/HDL-c, and LDL-c/HDL-c, were screened, which can effectively predict the risk of developing IR in obese children and adolescents, and the nomogram model has an eligible diagnostic value., (© 2023. The Author(s).)

Photosynthetic bacteria wastewater treatment is an efficient water pollution treatment method, but photosynthetic bacteria fermentation is a multivariable, non-linear, and time-varying process. So it is difficult to establish an accurate model. Aiming at the difficulty of online measurement of key parameters, such as bacterial concentration and matrix concentration in photosynthetic bacteria fermentation process, an improved ant colony algorithm least squares support vector machine (AC-LSSVM) soft sensing model method is proposed in this paper. Firstly, the virtual sensing subsystem of the photosynthetic bacteria fermentation process is proposed, with measurable parameters as input and unmeasurable key parameters as output, and the left inverse soft sensing model of virtual sensing is constructed. Then, the ant colony algorithm can quickly find the shortest path to optimize the parameters of the traditional PI regulation, to improve the dynamic performance and accuracy of parameter measurement in the fermentation process. After that, the ant colony algorithm is used to optimize penalty parameters C and kernel parameters σ of LSSVM, which effectively avoids the local optimization and improves the computing power and global optimization ability. Finally, the soft sensing prediction model of the photosynthetic bacteria fermentation process based on AC-LSSVM is established. Compared with SVM and LSSVM prediction models, the root mean square error of bacterial concentration and matrix concentration based on the AC-LSSVM model are 0.468 and 0.126, respectively. The simulation analysis shows that this model has less error and better prediction ability, and it can meet the needs of online prediction of key parameters of photosynthetic bacteria fermentation.

Purpose: This study aimed to explore the characteristics of resting energy expenditure (REE) and lipid metabolism during incremental load exercise in obese children and adolescents with insulin resistance (IR) to provide evidence for exercise intervention in obese children and adolescents with IR. Method: From July 2019 to August 2021, 195 obese children and adolescents aged 13-17 were recruited through a summer camp. The participants were divided into IR ( n = 67) and no-IR (without insulin resistance, n = 128) groups and underwent morphology, blood indicators, body composition, and resting energy consumption gas metabolism tests. Thirty participants each were randomly selected from the IR and no-IR groups to carry out the incremental treadmill test. Results: Significant metabolic differences in resting and exercise duration were found between the IR and no-IR groups. In the resting state, the resting metabolic equivalents (4.33 ± 0.94 ml/min/kg vs. 3.91 ± 0.73 ml/min/kg, p = 0.001) and REE (2464.03 ± 462.29 kcal/d vs. 2143.88 ± 380.07 kcal/d, p < 0.001) in the IR group were significantly higher than in the no-IR group. During exercise, the absolute maximal fat oxidation (0.33 ± 0.07 g/min vs. 0.36 ± 0.09 g/min, p = 0.002) in the IR group was significantly lower than in the no-IR group; maximal fat oxidation intensity (130.9 ± 8.9 bpm vs. 139.9 ± 7.4 bpm, p = 0.040) was significantly lower in the IR group. Conclusion: Significant resting and exercise metabolic differences were found between obese IR and no-IR children and adolescents. Obese IR children and adolescents have higher REE and lower maximal fat oxidation intensity than obese no-IR children and adolescents., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Youxiang, Lin, Zekai and Weijun.)

Andrographolide(ADE) has been demonstrated to inhibit tumor growth through direct cytotoxicity on tumor cells. However, its potential activity on tumor microenvironment (TME) remains unclear. Tumor-associated macrophages (TAMs), composed mainly of M2 macrophages, are the key cells that create an immunosuppressive TME by secretion of cytokines, thus enhancing tumor progression. Re-polarized subpopulations of macrophages may represent vital new therapeutic alternatives. Our previous studies showed that ADE possessed anti-metastasis and anoikis-sensitization effects. Here, we demonstrated that ADE significantly suppressed M2-like polarization and enhanced M1-like polarization of macrophages. Moreover, ADE inhibited the migration of M2 and tube formation in HUVECs under M2 stimulation. In vivo studies showed that ADE restrained the growth of MDA-MB-231 and HCC1806 human breast tumor xenografts and 4T-1 mammary gland tumors through TAMs. Wnt5a/β-catenin pathway and MMPs were particularly associated with ADE's regulatory mechanisms to M2 according to RNA-seq and bioinformatics analysis. Moreover， western blot also verified the expressions of these proteins were declined with ADE exposure. Among the cytokines released by M2, PDGF-AA and CCL2 were reduced. Our current findings for the first time elucidated that ADE could modulate macrophage polarization and function through Wnt5a signaling pathway, thereby playing its role in inhibition of triple-negative breast cancer., (© 2022 The Authors. Phytotherapy Research published by John Wiley & Sons Ltd.)

Background:  Intracranial aneurysms may be misdiagnosed with other vascular lesions such as vascular loops, infundibulum, or the stump of an occluded artery (very rare and reported compromising only the middle cerebral artery and the posterior circulation territory). Our aim was to describe a unique case of occlusion of an anterior cerebral artery mimicking a cerebral aneurysm in a probable moyamoya disease patient, and to highlight its clinical presentation, diagnosis, and management, and to perform an extensive literature review., Case:  A 67-year-old man suffering from recurrent dizziness for 3 months. Previous medical history was unremarkable. Brain magnetic resonance angiography (MRA) and digital subtraction angiography (DSA) demonstrated occlusion of the right middle cerebral artery (MCA) associated with a "probable moyamoya disease" and an aneurysm-like shadow protruding lesion at the anterior communicating artery (AcomA). Perfusion images showed ischemia along the right temporo-occipital lobe. Due to MCA occlusion with perfusion deficits and unspecific symptoms, we offered a right side encephalo-duro-myo-synangiosis (EDMS) and clipping of the AcomA aneurysm in one session. Intraoperatively, there was no evidence of the AcomA aneurysm; instead, this finding corresponded to the stump of the occluded right anterior cerebral artery (A1 segment). This segment appeared to be of yellowish color due to atherosclerosis and lacked blood flow. The patient underwent as previously planned a right side EDMS and the perioperative course was uneventful without the presence of additional ischemic attacks., Conclusion:  Arterial branch occlusions can sometimes present atypical angiographic characteristics that can mimic a saccular intracranial aneurysm. It is relevant to consider this radiographic differential diagnosis, especially when aneurysm treatment is planned., Competing Interests: None declared., (Thieme. All rights reserved.)

Transarterial chemoembolization (TACE) is the major treatment for advanced hepatocellular carcinoma (HCC), but it may cause hypoxic environment, leading to rapid progression after treatment. Here, using high-throughput sequencing on different models, S100 calcium binding protein A9 (S100A9) is identified as a key oncogene involved in post-TACE progression. Depletion or pharmacologic inhibition of S100A9 significantly dampens the growth and metastatic ability of HCC. Mechanistically, TACE induces S100A9 via hypoxia-inducible factor 1α (HIF1A)-mediated pathway. S100A9 acts as a scaffold recruiting ubiquitin specific peptidase 10 and phosphoglycerate mutase family member 5 (PGAM5) to form a tripolymer, causing the deubiquitination and stabilization of PGAM5, leading to mitochondrial fission and reactive oxygen species production, thereby promoting the growth and metastasis of HCC. Higher S100A9 level in HCC tissue or in serum predicts a worse outcome for HCC patients. Collectively, this study identifies S100A9 as a key driver for post-TACE HCC progression. Targeting S100A9 may be a promising therapeutic strategy for HCC patients., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Background: Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus (DM). MicroRNA (miR)-218 is associated with the development of diabetes. Besides, sprouty-related EVH1 domain containing 2 (SPRED2), the downstream target of miR-218, is involved in insulin resistance and inflammation., Objectives: Since inflammation plays a key role in DN, and SPRED2 is known to facilitate cell autophagy, the present study aimed to investigate the role and molecular mechanism of miR-218 and SPRED2-mediated autophagy in high glucose (HG)-induced renal tubular epithelial cells using an in vitro model., Material and Methods: The HK-2 cells were cultured in 5.5 mM or 30 mM D-glucose medium. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of miR-218 and SPRED2. Western blotting was performed to calculate the levels of SPRED2, inflammatory cytokines, autophagy-related and apoptosis-related proteins. Reactive oxygen species (ROS) level was evaluated using cellular ROS assay kit, superoxide dismutase (SOD) activity was detected using SOD activity assay kit, and malondialdehyde (MDA) content was measured using lipid peroxidation. The levels of interleukin (IL)-1β, IL-6, IL-4, and tumor necrosis factor alpha (TNF-α) were detected with enzyme-linked immunosorbent assay (ELISA). Cell apoptosis was evaluated using flow cytometry analysis. The targeting relationship between miR-218 and SPRED2 was identified with a luciferase reporter. The LC3-II expression was detected with immunofluorescence., Results: The miR-218 expression was upregulated and SPRED2 expression was downregulated in HG-induced HK-2 cells. The miR-218 was proven to target SPRED2 and negatively regulate SPRED2 expression. Besides, downregulated miR-218 alleviated inflammatory response, oxidative stress and cell apoptosis, but aggravated autophagy. We also showed that downregulated SPRED2 reversed the effect of miR-218 on inflammation, cell apoptosis and autophagy in HG-induced HK-2 cells., Conclusions: The miR-218 can promote oxidative stress and inflammatory response in HG-induced renal tubular epithelial cells by inhibiting SPRED2-mediated autophagy. This study might bring novel understanding for molecular mechanism of DN.

Recently, the albumin-bilirubin (ALBI) score, a continuous index consisting of only albumin and bilirubin, has been developed for objectively assessing liver function in patients with hepatocellular carcinoma (HCC). However, the ALBI score was arbitrarily categorized into three ALBI grades based on two artificially predetermined cutoff points with no explanation and statistical grounds, causing a considerable loss of discriminatory ability. This study aims to propose a modified ALBI (mALBI) grade for offering a detailed evaluation of hepatic reserve and specify its role during clinical practice in the HCC setting. The study population comprised 3540 HCC patients treated with mainstream therapies including hepatectomy (n=2056), thermal ablation (n=550), and transcatheter arterial chemoembolization (n=934) from 2002 to 2017. The ALBI score was stratified into four mALBI grades through a recently proposed statistical method aiming to select the optimal cutoff points of a continuous predictive variable by maximizing the discriminative ability in a multivariable Cox regression model. The mALBI grade had an overall better discriminatory ability than the ALBI grade in predicting overall survival through Harrell's C-index (0.614 vs. 0.598, P<0.001). Both visual inspections of Kaplan-Meier curves and calculation of hazard ratios displayed a more subtle evaluation of liver function using the mALBI grade. Moreover, the newly identified cut-point (ALBI score = -2.29) between the mALBI grade 2a and 2b was much closer to a 30% retention rate of indocyanine green at 15 minutes, an indicator for the performance of a subsegmentectomy. The newly proposed mALBI grade provides a more subtle assessment of liver function to guide clinical decision-making and predicts the prognosis of HCC patients more accurately than the original ALBI grade., Competing Interests: None., (AJCR Copyright © 2022.)

Objectives  During craniotomy for cerebellopontine angle (CPA) lesions, the exact exposure of the margin of the venous sinuses complex remains an essential but risky part of the procedure. Here, we revealed the exact position of the asterion and sinus complex by combining preoperative image information and intraoperative cranial landmarks, and analyzed their clinic-image relationship. Methods  Ninety-four patients who underwent removal of vestibular schwannoma (VS) through retrosigmoid craniotomies were enrolled in the series. To determine the exact location of the sigmoid sinus and the transverse sinus and sigmoid sinus junction (TSSJ), we used preoperative images, such as computed tomography (CT) and/or magnetic resonance imaging (MRI) combined with intraoperative anatomical landmarks. The distance between the asterion and the sigmoid sinus was measured using MRI T1 sequences with gadolinium and/or the CT bone window. Results  In 94 cases of retrosigmoid craniotomies, the asterion lay an average of 12.71 mm on the posterior to the body surface projection to the TSSJ. Intraoperative cranial surface landmarks were used in combination with preoperative image information to identify the distance from the asterion to the sigmoid sinus at the transverse sinus level, allowing for an appropriate initial burr hole (the margin of the TSSJ). Conclusion  By combining intraoperative anatomical landmarks and preoperative image information, the margin of the TSSJ, in particular, the inferior margin of the transverse sinus, can be well and thoroughly identified in the retrosigmoid approach., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

Thermal ablation is a main curative therapy for early-stage hepatocellular carcinoma (HCC). However, insufficient ablation has been shown to promote HCC progression. E3 ligases have been approved to play important roles in malignant tumors. Whether E3 ligases are involved in HCC progression caused by insufficient ablation remains unclear. Herein, using RNA-sequencing coupled with an in vitro loss-of-function screen, we found that the E3 ligase Neuronal Precursor cell-expressed Developmentally Downregulated 4 (Nedd4) was upregulated in HCC insufficient ablation tissues and promoted HCC cells migration. The upregulation of Nedd4 was induced by METTL14-mediated N 6 -methyladenosine modification after sublethal heat treatment. Knockdown of Nedd4 inhibited HCC metastasis and growth in vitro and in vivo. Mechanistically, Nedd4 enhanced TGF-β signal transduction mediated tumor progression by directly binding to TGF-β type I receptor (TGFBR1) and forming K27-linked ubiquitin at Lysine 391. Additionally, the adverse effect on HCC of sublethal heat treatment was mediated by Nedd4. Clinically, high Nedd4 expression was positively correlated with aggressive tumor phenotypes and poor prognosis in HCC patients. Patient-derived xenograft (PDX) model confirmed this conclusion. Collectively, this study demonstrated that Nedd4 induced by insufficient ablation plays a crucial role in promoting HCC progression and provides a novel therapeutic target for HCC., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Sucrose non-fermenting 1 (SNF1)-associated protein kinase 2 (SnRK2) proteins belong to a relatively small family of plant-specific serine/threonine (Ser/Thr) protein kinases. SnRK2s participate in the abscisic acid (ABA) signaling pathway and play important roles in many biotic and abiotic stresses. At present, no SnRK2 gene has been reported in quinoa, and the recently published genome for this species provides an opportunity to identify and characterize the SnRK2 gene family., Results: We identified 13 SnRK2 genes in the C. quinoa genome by bioinformatics analysis. Based on their phylogenetic relationships, these genes were divided into three subfamilies, similar to the situation in other plant species. Gene duplication analysis showed that there were seven pairs of homologous genes in the CqSnRK2 family, and that purifying selection played an important role in the evolution of SnRK2 genes. Gene structure analysis showed that the first exon in the SnRK2 family genes has the same length as the last exon, and that CqSnRK2 genes in the same subfamily have similar gene structures. Sequence analysis showed that the N-terminal region contains three highly conserved motifs. In addition, many kinds of cis-elements were identified in the promoter region of CqSnRK2, including those for hormone responses, stress responses, and tissue-specific expression. Transcription data analysis and qRT-PCR results showed that CqSnRK2 has different expression patterns in roots, stems, and leaves, and responded to biotic and abiotic stresses such as low temperature, salt, drought, and abscisic acid (ABA). In addition, we found that the protein encoded by CqSnRK2.12 was localized to the cytoplasm and nucleus, and there was no self-activation. The results of CqSnRK2.12 overexpression showed that transgenic Arabidopsis thaliana lines had increased drought tolerance compared to the controls., Conclusion: The results of our study provide references for further studies on the evolution, function, and expression of the SnRK2 gene family in quinoa., (© 2022. The Author(s).)

Astrocytes are increasingly recognized to play an active role in learning and memory, but whether neural inputs can trigger event-specific astrocytic Ca 2+ dynamics in real time to participate in working memory remains unclear due to the difficulties in directly monitoring astrocytic Ca 2+ dynamics in animals performing tasks. Here, using fiber photometry, we showed that population astrocytic Ca 2+ dynamics in the hippocampus were gated by sensory inputs (centered at the turning point of the T-maze) and modified by the reward delivery during the encoding and retrieval phases. Notably, there was a strong inter-locked and antagonistic relationship between the astrocytic and neuronal Ca 2+ dynamics with a 3-s phase difference. Furthermore, there was a robust synchronization of astrocytic Ca 2+ at the population level among the hippocampus, medial prefrontal cortex, and striatum. The inter-locked, bidirectional communication between astrocytes and neurons at the population level may contribute to the modulation of information processing in working memory., (© 2021. Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences.)

The P-O bond of epimerized alkoxyl phosphine-borane was cleaved by naphthalene-lithium, to form two diastereomers of P-anions in a ratio of 86 : 14, which was then converted to secondary phosphine-borane via acidification, and to tertiary phosphines with alkyl halides with enhanced 96 : 4 dr. The isolated tertiary phosphine containing hydroxyl (in >99 : 1 dr) was converted to multi-stereogenic tertiary phosphines via O -alkylation with alkylene dihalides.

Cardiac hypertrophy occurs initially in response to an increased cardiac load as a compensatory mechanism to maintain cardiac output. However, sustained pathological hypertrophy can develop into heart failure and cause sudden death. Fibroblast growth factor 20 (FGF20) is a member of the fibroblast growth factor family, which involved in apoptosis, aging, inflammation, and autophagy. The precise function of FGF20 in pathological cardiac hypertrophy is unclear. In this study, we demonstrated that FGF20 was significantly decreased in response to hypertrophic stimulation. In contrast, overexpression of FGF20 protected against pressure overload-induced cardiac hypertrophy. Mechanistically, we found that FGF20 upregulates SIRT1 expression, causing deacetylation of FOXO1; this effect promotes the transcription of downstream antioxidant genes, thus inhibits oxidative stress. In content, the anti-hypertrophic effect of FGF20 was largely counteracted in SIRT1-knockout mice, accompanied by an increase in oxidative stress. In summary, our findings reveal a previously unknown protective effect of FGF20 on pathological cardiac hypertrophy by reducing oxidative stress through activation of the SIRT1 signaling pathway. FGF20 is a potential novel molecular target for preventing and treating pressure overload-induced myocardial injury., (© 2022. The Author(s).)

Purpose: To study the morphology of the posterior lens cortex and posterior capsules (PCs) in pediatric patients with posterior lens opacities using intraoperative optical coherence tomography (iOCT)., Setting: Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China., Design: Prospective observational study., Methods: Pediatric patients with posterior lens opacities were imaged using iOCT during cataract surgery. The morphology of the posterior lens cortex and PC, along with the common patterns to indicate PC integrity, was assessed. Moreover, PC rent during surgery was observed., Results: A total of 62 eyes from 53 patients were included. The mean age of patients was 3.8 years. 4 morphological variants of posterior lens opacity were observed: type I (34/62 [54.8%]) with an intact PC; type II (20/62 [32.3%]) with an intact PC, which protruded into the anterior vitreous; type III (3/62 [4.8%]) with a deficient PC and an inability to delineate the PC; and type IV (5/62 [8.1%]) with dense opacity and an inability to characterize the posterior cortex and PC. Phacoemulsification could be performed in types I and II. In types III and IV, manual nucleus removal was performed instead of phacoemulsification. 3 cases (100%) of type III PC dehiscence developed during surgery, whereas no cases developed PC dehiscence of other types., Conclusions: The morphology of the PC and posterior lens cortex in pediatric posterior lens opacities could be categorized, and PC integrity could be assessed using iOCT, which was useful to guide surgical strategies and increase safety in pre-existing PC dehiscence in pediatric cataract surgery., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of ASCRS and ESCRS.)

Circular RNAs (circRNAs) are involved in the development and progression of diabetic cardiomyopathy (DCM). However, the specific function and underlying mechanism of circ&#95;0071269 in DCM remains unclear. In our study, mRNA and miRNA expression was detected by real-time quantitative PCR (qRT-PCR). RNase R and actinomycin D treatment were applied to test the characteristics of circ&#95;0071269. Cell Counting Kit-8 (CCK-8) assay, lactate dehydrogenase (LDH) and enzyme-linked immunosorbent assay (ELISA) kits were performed to determine the cell viability, cell LDH content and interleukin (IL)-1β and IL-18 levels, respectively. Cell death rate was determined by Flow cytometry, and Western blotting was for the protein expression levels. In addition, luciferase reporter and RNA pull-down assays were performed to confirm the binding relationship between miR-145 and circ&#95;0071269 or gasdermin A (GSDMA). Echocardiography, Hematoxylin and Eosin (HE) Staining, and Immunohistochemical (IHC) Staining were performed to evaluate myocardial damage in vivo . We found that circ&#95;0071269 was significantly overexpressed in H9c2 cells upon treatment with high glucose. Knockdown of circ&#95;0071269 promoted cell viability and inhibited the inflammatory response, cytotoxicity, and pyroptosis of H9c2 cells in vitro . Moreover, circ&#95;0071269 sponges miR-145 to upregulate GSDMA. A miR-145 inhibitor antagonized the effects of circ&#95;0071269 knockdown on the cellular functions of H9c2 cells, while the effects of miR-145 were abrogated by the overexpression of GSDMA. Meanwhile, knockdown of circ&#95;0071269 attenuated cardiac dysfunction of DM mice. Hence, circ&#95;0071269 may promote the development of DCM through the miR-145/GSDMA axis and thus provide a novel marker for the treatment of DCM.

Background: Chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) are two common malignant disorders in leukemia. Although potent drugs are emerging, CML and AML may still relapse after the drug treatment is stopped. N6-methyladenosine (m6A) and lncRNAs play certain roles in the occurrence and development of tumors, but m6A-modified LncRNAs in ML remain to be further investigated., Methods: In this study, we extracted and analyzed the TCGA gene expression profile of 151 ML patients and the clinical data. On this basis, we then evaluated the immune infiltration capacity of ML and LASSO-penalized Cox analysis was applied to construct the prognostic model based on m6A related lncRNAs to verify the prognostic risk in clinical features of ML. Quantitative reverse transcription PCR was used to detect the expression level of LncRNA in in ML cell lines K562, MOLM13 and acute monocytic leukemia cell line THP-1., Results: We found 70 m6A-related lncRNAs that were related to prognosis, and speculated that the content of stromal cells and immune cells would correlate with the survival of patients with ML. Next, Prognostic risk model of m6A-related lncRNAs was validated to have excellent consistency in clinical features of ML. Finally, we verified the expression levels of CRNDE, CHROMR and NARF-IT1 in ML cell lines K562, MOLM13 and acute monocytic leukemia cell line THP-1, which were significant., Conclusions: The research provides clues for the prognosis prediction of ML patients by using the m6A-related lncRNAs model we have created, and clarifies the accuracy and authenticity of it., (© 2021. The Author(s).)

Deguelin is a rotenoid of the flavonoid family, which can be extracted from Lonchocarpus, Derris, or Tephrosia. It possesses the inhibition of cancer cell proliferation by inducing apoptosis through regulating the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway, the NF-κB signaling pathway, the Wnt signaling pathway, the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway and epidermal growth factor receptor (EGFR) signaling, activating the p38 mitogen-activated protein kinase (MAPK) pathway, repression of Bmi1, targeting cyclooxygenase-2 (COX-2), targeting galectin-1, promotion of glycogen synthase kinase-3β (GSK3β)/FBW7-mediated Mcl-1 destabilization and targeting mitochondria via down-regulating Hexokinases II-mediated glycolysis, PUMA-mediation, which are some crucial molecules which modulate closely cancer cell growth and metastasis. Deguelin inhibits tumor cell propagation and malignant transformation through targeting angiogenesis, targeting lymphangiogenesis, targeting focal adhesion kinase (FAK), inhibiting the CtsZ/FAK signaling pathway, targeting epithelial-mesenchymal transition (EMT), the NF-κB signaling pathway, regulating NIMA-related kinase 2 (NEK2). In addition, deguelin possesses other biological activities, such as targeting cell cycle arrest, modulation of autophagy, inhibition of hedgehog pathway, inducing differentiation of mutated NPM1 acute myeloid leukemia etc. Therefore, deguelin is a promising chemopreventive agent for cancer therapy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Cardiac surgery is associated with a substantial risk of major adverse events. Although carbon dioxide (CO 2 )-derived variables such as venous-to-arterial CO 2 difference (ΔPCO 2 ), and PCO 2 gap to arterial-venous O 2 content difference ratio (ΔPCO 2 /C (a-cv) O 2 ) have been successfully used to predict the prognosis of non-cardiac surgery, their prognostic value after cardiopulmonary bypass (CPB) remains controversial. This hospital-based study explored the relationship between ΔPCO 2 , ΔPCO 2 /C (a-cv) O 2 and organ dysfunction after CPB. Methods: We prospectively enrolled 114 intensive care unit patients after elective cardiac surgery with CPB. Patients were divided into the organ dysfunction group (OI) and non-organ dysfunction group (n-OI) depending on whether organ dysfunction occurred or not at 48 h after CPB. ΔPCO 2 was defined as the difference between central venous and arterial CO 2 partial pressure. Results: The OI group has 37 (32.5%) patients, 27 of which (23.7%) had one organ dysfunction and 10 (8.8%) had two or more organ dysfunctions. No statistical significance was found ( P = 0.84) for ΔPCO 2 in the n-OI group at intensive care unit (ICU) admission (9.0, 7.0-11.0 mmHg), and at 4 (9.0, 7.0-11.0 mmHg), 8 (9.0, 7.0-11.0 mmHg), and 12 h post admission (9.0, 7.0-11.0 mmHg). In the OI group, ΔPCO 2 also showed the same trend [ICU admission (9.0, 8.0-12.8 mmHg) and 4 (10.0, 7.0-11.0 mmHg), 8 (10.0, 8.5-12.5 mmHg), and 12 h post admission (9.0, 7.3-11.0 mmHg), P = 0.37]. No statistical difference was found for ΔPCO 2 /C (a-cv) O 2 in the n-OI group ( P = 0.46) and OI group ( P = 0.39). No difference was detected in ΔPCO 2 , ΔPCO 2 /C (a-cv) O 2 between groups during the first 12 h after admission ( P > 0.05). Subgroup analysis of the patients with two or more failing organs compared to the n-OI group showed that the predictive performance of lactate and Base excess (BE) improved, but not of ΔPCO 2 and ΔPCO 2 /C (a-cv) O 2 . Regression analysis showed that the BE at 8 h after admission (odds ratio = 1.37, 95%CI: 1.08-1.74, P = 0.009) was a risk factor for organ dysfunction 48 h after CBP. Conclusion : ΔPCO 2 and ΔPCO 2 /C (a-cv) O 2 cannot be used as reliable indicators to predict the occurrence of organ dysfunction at 48 h after CBP due to the pathophysiological process that occurs after CBP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhang, Zheng, Chu, Jiang, Wang, Zhang, Qian, Yang, Zhang, Tung and Lin.)

Rosa roxburghii Tratt. is widely applied in food, cosmetics, and traditional medicine, and has been demonstrated to possess diverse bioactivities. Plant endophytic fungi are important microbial resources with great potential for application in many fields. They not only establish mutualistic symbiosis with host plants but also produce a variety of bioactive compounds. Therefore, in the present study, endophytic fungi were isolated from R. roxburghii , the diversity and antimicrobial activities were evaluated. As a result, 242 strains of endophytic Sordariomycetes were successfully isolated. Multigene phylogenetic analyses showed that these isolates included eight orders, 19 families, 33 genera. The dominant genera were Diaporthe (31.4%), Fusarium (14.4%), Chaetomium (7.9%), Dactylonectria (7.0%), Graphium (4.5%), Colletotrichum (4.1%), and Clonostachys (4.1%). For different tissues of R. roxburghii , alpha diversity analysis revealed that the diversity of fungal communities decreased in the order of root, fruit, stem, flower, leaf, and seed, and Clonostachys and Dactylonectria exhibited obvious tissue specificity. Meanwhile, functional annotation of 33 genera indicated that some fungi have multitrophic lifestyles combining endophytic, pathogenic, and saprophytic behavior. Additionally, antimicrobial activities of endophytic Sordariomycetes against Lasiodiplodia theobromae , Botryosphaeria dothidea , Colletotrichum capsici , Pyricularia oryzae , Rhizoctonia solani , Fusarium oxysporum , Pseudomonas syringae , Pantoea agglomerans , Staphylococcus aureus , Bacillus subtilis , Escherichia coli , and Pseudomonas aeruginosa were screened. Dual culture test assays showed that there were 40 different endophytic species with strong inhibition of at least one or moderate inhibition of two or more against the 12 tested strains. The results from the filter paper diffusion method suggested that extracellular metabolites may be more advantageous than intracellular metabolites in the development of antimicrobial agents. Eleven isolates with good activities were screened. In particular, Hypomontagnella monticulosa HGUP194009 and Nigrospora sphaerica HGUP191020 have shown promise in both broad-spectrum and intensity. Finally, some fungi that commonly cause disease have been observed to have beneficial biological activities as endophytic fungi. In conclusion, this study showed the species composition, alpha diversity, and lifestyle diversity of endophytic Sordariomycetes from R. roxburghii and demonstrated these isolates are potential sources for exploring antimicrobial agents., Competing Interests: G-CT was employed by Food Safety and Nutrition (Guizhou) Information Technology Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhang, Wei, Li, Luo, Jia, Zeng, Jiang and Tao.)

Umbilical cord mesenchymal stem cells (UCMSCs) have been identified as a potentially ideal cell type for use in regenerative therapeutic contexts owing to their excellent paracrine secretory abilities and other desirable properties. Previous work has shown that stem cell-derived exosomes can effectively reduce skin aging, but few studies have specifically focused on the role of UCMSC-derived exosomes in this context. In this study, we isolated exosomes derived from UCMSCs grown in a three-dimensional culture system and explored their ability to modulate the photo-aging of HaCaT keratinocytes. Cell viability and proliferation were assessed using CCK8 assay, whereas wound healing and transwell assays were used to assess cell migratory capabilities. UVB irradiation (60 mJ/cm 2 ) was used to induce photo-aging of HaCaT cells. TUNEL and SA-β-Gal staining were used to explore HaCaT cell apoptosis and senescence, respectively, whereas real-time quantitative PCR was used to assess the expression of relevant genes at the mRNA level. We found that UCMSC-derived exosomes were able to enhance normal HaCaT cell proliferation and migration while also inhibiting UVB-induced damage to these cells. These exosomes also reduced HaCaT cell apoptosis and senescence, increasing collagen type I expression and reducing matrix metalloproteinase (MMP1) expression in photo-aged HaCaT cells. Together, these findings indicate that UCMSC-derived exosomes have the potential to be used therapeutically to suppress skin aging.

Objective: In this study, we focused on the potential mechanism of miRNAs carried by human umbilical cord mesenchymal stem cells-derived exosomes (hUCMSCs-exo) in breast cancer (BC). Methods: RT-qPCR was conducted for the expression of miR-224-5p and HOXA5 in tissues and cells. After co-culture of exosomes and MCF-7 or MDA-MB-231 cells, the cell proliferation was observed by MTT and cell colony formation assay, while apoptosis was measured by flow cytometry. In addition, the expression of HOXA5 and autophagy pathway-related proteins LC3-II, Beclin-1 and P62 was detected by western blotting. And immunofluorescence was applied for detection of LC3 spots. The binding of miR-224-5p to HOXA5 was verified by the luciferase reporter gene assay and RNA-binding protein immunoprecipitation assay. Finally, in vivo experiment was performed to investigate the effect of miR-224-5p on BC growth. Results: MiR-224-5p was up-regulated and HOXA5 was down-regulated in BC tissues and cells. HOXA5 was confirmed to be the target gene of miR-224-5p. MiR-224-5p carried by hUCMSCs-exo was able to promote the proliferation and autophagy of BC cells, while inhibited apoptosis. Bases on xenograft models in nude mice, it was also revealed that miR-224-5p carried by hUCMSCs-exo could regulate autophagy and contribute to the occurrence and development of BC in vivo . Conclusion: MiR-224-5p carried by hUCMSCs-exo can regulate autophagy via inhibition of HOXA5, thus affecting the proliferation and apoptosis of BC cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wang, Wang, Zhao, Chen, Lin, Zhang and Li.)

The COVID-19 pandemic caused by SARS-CoV-2 is threating global health. Inhibiting interaction of the receptor-binding domain of SARS-CoV-2 S protein (S RBD ) and human ACE2 receptor is a promising treatment strategy. However, SARS-CoV-2 neutralizing antibodies are compromised by their risk of antibody-dependent enhancement (ADE) and unfavorably large size for intranasal delivery. To avoid these limitations, we demonstrated an aptamer blocking strategy by engineering aptamers' binding to the region on S RBD that directly mediates ACE2 receptor engagement, leading to block SARS-CoV-2 infection. With aptamer selection against S RBD and molecular docking, aptamer CoV2-6 was identified and applied to prevent, compete with, and substitute ACE2 from binding to S RBD . CoV2-6 was further shortened and engineered as a circular bivalent aptamer CoV2-6C3 (cb-CoV2-6C3) to improve the stability, affinity, and inhibition efficacy. cb-CoV2-6C3 is stable in serum for more than 12 h and can be stored at room temperature for more than 14 days. Furthermore, cb-CoV2-6C3 binds to S RBD with high affinity (K d =0.13 nM) and blocks authentic SARS-CoV-2 virus with an IC 50 of 0.42 nM., (© 2021 Wiley-VCH GmbH.)

Introduction: Breast cancer is the main reason for cancer-related deaths in women and the most common malignant cancer among women. In recent years, immunosuppressive factors have become a new type of treatment for cancer. However, there are no effective biomarkers for breast cancer immunotherapy. Therefore, exploring immune-related biomarkers is presently an important topic in breast cancer., Methods: Gene expression profile data of breast cancer from The Cancer Genome Atlas (TCGA) was downloaded. Scale-free gene co-expression networks were built with weighted gene co-expression network analysis. The correlation of genes was performed with Pearson's correlation values. The potential associations between clinical features and gene sets were studied, and the hub genes were screened out. Gene Ontology and gene set enrichment analysis were used to reveal the function of hub gene in breast cancer. The gene expression profiles of GSE15852, downloaded from the Gene Expression Omnibus database, were used for hub gene verification. In addition, candidate biomarkers expression in breast cancer was studied. Survival analysis was performed using Log rank test and Kaplan-Meier. Immunohistochemistry was used to analyze the expression of CCNA2 ., Results: A total of 6 modules related to immune cell infiltration were identified via the average linkage hierarchical clustering. According to the threshold criteria (module membership >0.9 and gene significance >0.35), a significant module consisting of 13 genes associated with immune cells infiltration were identified as candidate hub genes after performed with the human protein interaction network. And 3 genes with high correlation to clinical traits were identified as hub genes, which were negatively associated with the overall survival. Among them, the expression of CCNA2 was increased in metastatic breast cancer compare with non-metastatic breast cancer, who underwent immunotherapy. Immunohistochemistry results showed that CCNA2 expression in carcinoma tissues was elevated compared with normal control., Discussion: CCNA2 identified as a potential immune therapy marker in breast cancer, which were first reported here and deserved further research., Competing Interests: The authors declare no potential conflicts of interest., (© 2021 Wang et al.)

Background: Telomeres undergo shortening with each cell division, which could be accelerated by infection. The association between virus infection and telomere length is poorly understood. In the present study, we investigated the putative associations between leukocyte telomere length (TL), cytomegalovirus (CMV) infection, and C-reactive protein (CRP) in a national representative sample of noninstitutionalized population., Methods: We analyzed data that was collected in a cross-sectional setting, where 3,987 participants were enrolled with available data on telomere length. The association between telomere length with previous CMV infection and CRP was analyzed using multivariable linear regression models. We further tested if obesity, measured by body mass index (BMI), and smoking could modify this relationship., Results: In total, around 46% percent of the study population were men and 54% were women. Average ages were 35.1 years for men and 35.0 years for women. One unit increase of CMV antibody IgG titer was associated with -0.07 (95% confidence interval: -0.12, -0.01) unit decrease of leukocyte TL when sex was adjusted for. After additionally adjusting for BMI and smoking status, the magnitude of the association was only slightly decreased to -0.06 (95% confidence interval: -0.11, -0.01). The effect sizes were comparable after additionally adjusting for CRP. These analyses imply that previous CMV infection affects leukocyte TL through pathways other than CRP., Conclusions: Previous CMV infection was associated with shorter leukocyte TL. This association was independent of CRP., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2021 Zhu Lin et al.)

The ongoing pandemic of coronavirus disease 2019 poses a great threat to human beings. Although numerous patients have recovered, re-positive cases have been reported in several countries. Till now, we still know very little about the disease and its pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, more attention should be paid to the following aspects, such as post-discharge surveillance, asymptomatic infection, re-evaluation of influenza-like symptoms, and dynamic monitoring of genomic mutation of SARS-CoV-2., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest involved., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Purpose: Whether or not young patients with squamous cell carcinoma of oral cavity (OC-SCC) have a difference in prognosis remains a controversy. This study aimed to analyze the clinical characteristics and difference of survival rates between adult patients less than 40 years of age and those 40 years of age and older., Methods: A retrospective analysis was conducted using the database of patients diagnosed with OC-SCC between 1990 and 2013 in the Sun Yat-sen University Cancer Center, but patients older than 85 years, younger than 18 years, or died within 6 months of diagnosis were excluded. Patients were categorized into two groups: the young group (< 40 years of age) and the older group (≥ 40 years of age). Cox regression, survival and subgroups analyses were performed. The primary endpoints included the rates of 5-year overall survival (OS) and disease-specific survival (DSS)., Results: A total of 1902 OC-SCC patients were identified. The percentage of female in the young group was significantly higher than that in the older group (40.27% vs 31.03%, p < 0.001). This study failed to find the difference in TNM classification or tumor stage between the two groups (p > 0.05). The young group was more likely to receive adjuvant radiotherapy and/or chemotherapy (42.48% vs 26.91%, p < 0.001). The 5-year OS rate (71% vs. 57%, p < 0.001) and DSS rate (72% vs 58%, p < 0.001) in patients under 40 years were significantly higher than those for the older group., Conclusion: Our findings suggested that OC-SCC in younger patients did not present at a more advanced stage. In addition, young age is an independent predictor for better survival.

Objective: To evaluate the effects of tube voltage on image quality in coronary CT angiography (CCTA), the estimated radiation dose, and DNA double-strand breaks (DSBs) in peripheral blood lymphocytes to optimize the use of CCTA in the era of low radiation doses., Materials and Methods: This study included 240 patients who were divided into 2 groups according to the DNA DSB analysis methods, i.e., immunofluorescence microscopy and flow cytometry. Each group was subdivided into 4 subgroups: those receiving CCTA only with different tube voltages of 120, 100, 80, or 70 kVp. Objective and subjective image quality was evaluated by analysis of variance. Radiation dosages were also recorded and compared., Results: There was no significant difference in demographic characteristics between the 2 groups and 4 subgroups in each group (all p > 0.05). As tube voltage decreased, both image quality and radiation dose decreased gradually and significantly. After CCTA, γ-H2AX foci and mean fluorescence intensity in the 120-, 100-, 80-, and 70-kVp groups increased by 0.14, 0.09, 0.07, and 0.06 foci per cell and 21.26, 9.13, 8.10, and 7.13 (all p < 0.05), respectively. The increase in the DNA DSB level in the 120-kVp group was higher than those in the other 3 groups (all p < 0.05), while there was no significant difference in the DSBs levels among these latter groups (all p > 0.05)., Conclusion: The 100-kVp tube voltage may be optimal for CCTA when weighing DNA DSBs against the estimated radiation dose and image quality, with further reductions in tube voltage being unnecessary for CCTA., Competing Interests: UJS is a consultant for and/or receives research support from Astellas, Bayer, Elucid BioImaging, General Electric, Guerbet, HeartFlow, and Siemens Healthineers. The other authors have no conflicts of interest to disclose., (Copyright © 2020 The Korean Society of Radiology.)

Heterostructures composed of superconductor and ferroelectrics (SC/FE) are very important for manipulating the superconducting property and applications. However, growth of high-quality superconducting iron chalcogenide films is challenging because of their volatility and FE substrate with rough surface and large lattice mismatch. Here, we report a two-step growth approach to get high-quality FeSe 0.5 Te 0.5 (FST) films on FE Pb(Mg 1/3 Nb 2/3 ) 0.7 Ti 0.3 O 3 with large lattice mismatch, which show superconductivity at only around 10 nm. Through a systematic study of structural and electric transport properties of samples with different thicknesses, a mechanism to grow high-quality FST is discovered. Moreover, electric-field-induced remarkable change of T c (superconducting transition temperature) is demonstrated in a 20 nm FST film. This work paves the way to grow high-quality films which contain volatile element and have large lattice mismatch with the substrate. It is also helpful for manipulating the superconducting property in SC/FE heterostructures.